An Unexpected Diastereoselective Synthesis of Novel Substituted Pyridines via One-Pot, Four-Component Reaction

Abstract

An efficient diastereoselective approach for the preparation of novel substituted pyridines has been developed through a one-pot, four-component reaction of easily available aromatic aldehydes, malononitrile, and 6,8-dimethyl-2-hydroxy-4H-pyrimido[1,2-a]pyrimidine-4-one, in appropriate alcohols at reflux in the presence of diisopropylethylamine (DIPEA) as organic base catalyst. Unexpected products were obtained in high to excellent yields using a simple workup procedure. The products synthesized showed high diastereoselectivity, and the stereochemistry was confirmed by X-ray diffraction analysis.

Key words

multicomponent reaction - diastereoselective synthesis - 6,8-dimethyl-2-hydroxy-4H-pyrimido[1,2-a]pyrimidine-4-one - malononitrile - 2-oxo-4-phenyl-1,2,3,4-tetrahydropyridine

• References and Notes

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• 25 General Procedure for the Synthesis of 4 A mixture of aromatic aldehyde (1, 1 mmol), malononitrile (2, 1 mmol, 660 mg), 6,8-dimethyl-2-hydroxy-4H-pyrimido[1,2-a]pyrimidin-4-one (3, 1 mmol, 192 mg), and DIPEA (5 mol%) was heated to reflux in the requisite alcohol (6 mL) for 2 h (the progress of the reaction was monitored by TLC). After completion of reaction, the mixture was allowed to cool to room temperature, and the precipitate was filtered off and washed with cold alcohol to afford the pure alkyl 6-amino-5-cyano-2-oxo-4-phenyl-1-pyrimidin-2-yl-1,2,3,4-tetrahydropyridine-3-carboxylate 4 (yields 85–95%). Representative Analytical Data Ethyl 6-Amino-5-cyano-1-(4,6-dimethylpyrimidin-2-yl)-2-oxo-4-phenyl-1,2,3,4-tetrahydropyridine-3-carboxylate (4a) White powder, 355 mg (91%); mp 207 °C; R_f = 0.52 (n-hexane–EtOAc, 1:1.5). IR (KBr): ν = 3448, 3324 (NH₂), 2195 (CN), 1743, 1721 (2 C=O), 1653 (C=N) cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 1.19 (t, 3 H, J = 7.0 Hz,OCH₂CH ₃), 2.54 (s, 6 H, 2 CH₃), 3.85 (d, 1 H, J = 7.7 Hz, CHC=O), 4.15–4.20 (m, 2 H, OCH ₂CH₃), 4.34 (d, 1 H, J = 7.7 Hz, CHAr), 4.91 (s, 2 H, NH₂), 7.10 (s, 1 H, CH=CCH₃), 7.26–7.38 (m, 5 H, H_Ar). ¹³C NMR (75 MHz, CDCl₃): δ = 13.98 (OCH₂ CH₃), 23.84 (2 CH₃), 40.28 (CHPh), 56.64 (CHC=O), 62.02 (CCN), 63.41 (CH₂O), 119.16 (C≡N), 120.42 (CH_Ar), 127.65 (2 CH _ortho ), 128.04 (CH _para ), 129.02 (2 CH _meta ), 138.38 (C_Ar), 152.20 (CNH₂), 155.16 (NC=N), 165.43 (C=O), 167.05 (C=O), 170.07 (2 CCH₃). MS: m/z (%) = 391 (4) [M⁺], 378 (69), 358 (64), 341 (18), 313 (100), 258 (68), 271 (63), 233 (62). 211 (48), 198 (63), 164 (65), 122 (66), 106 (71), 81 (61), 67 (70), 42 (64), 29 (65). Anal. Calcd for C₂₁H₂₁N₅O₃: C, 64.44; H, 5.41; N, 17.89. Found: C, 63.99; H, 5.39; N, 17.83. Ethyl 6-Amino-5-cyano-1-(4,6-dimethylpyrimidine-2-yl)-4-(3-nitrophenyl)-2-oxo-1,2,3,4-tetrahydropyridine-3-carboxylate(4b) White powder, 409 mg (94%); mp 211–212 °C; R_f = 0.40 (n-hexane–EtOAc, 1:1.5). IR (KBr): ν = 3452, 3350 (NH₂), 2185 (CN), 1747, 1717 (2 C=O), 1632 (C=N) cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 1.24 (t, 3 H, J = 4.5 Hz, OCH₂CH ₃), 2.56 (s, 6 H, 2 CH₃), 3.82 (d, 1 H, J = 7.79 Hz, CHC=O), 4.21–4.25 (m, 2 H, OCH ₂CH₃), 4.46 (d, 1 H, J = 7.79 Hz, CHAr), 5.11 (s, 2 H, NH₂), 7.12 (s, 1 H, CH=CCH₃), 7.26–8.31 (m, 4 H, H_Ar). ¹³C NMR (75 MHz, CDCl₃): δ = 14.02 (OCH₂ CH₃), 23.81 (2 CH₃), 40.15 (CHPh), 56.51 (CHC=O), 61.25 (CCN), 62.50 (CH₂O), 118.81 (C≡N), 120.60 (CH_Ar), 122.74 (CH _ortho ), 123.244 (CH _para ), 130.16 (CH _meta ), 134.12 (CH _ortho ), 140.83 (NC=N), 148.69 (C_Ar), 153.05 (CNH₂), 154.99 (CNO₂), 164.60 (C=O), 166.48 (C=O), 170.27 (2 CCH₃). MS: m/z (%) = 436 (14) [M⁺], 422 (72), 393 (71), 346 (100), 318 (71), 304 (69), 241 (42), 212 (32), 199 (72), 150 (71), 123 (73), 107 (74), 82 (50), 67 (72), 29 (74). Anal. Calcd for C₂₁H₂₀N₆O₅: C, 57.79; H, 4.62; N, 17.26. Found: C, 57.62; H, 4.27; N, 16.95.